The present invention is directed to methods for producing spray dried products. More particularly, one aspect of the present invention relates to methods for preparing solid materials utilizing a feedstock comprising an organic material in a composition comprising a non-solvent for the organic material to produce a spray-dried composition wherein the feedstock is provided at an elevated temperature and/or elevated pressure relative to ambient conditions. In accordance with particular embodiments of the invention, the feedstock comprises a polymer and a pharmaceutically active material.
Spray drying is a particle processing technology that transforms a liquid feedstock into a powder product by first spraying the feedstock to create droplets, and then evaporating the feedstock liquid through the use of a heated drying medium, typically air. The liquid feedstock can take the form of a solution, suspension, liquid-paste, or emulsion, and must be pumpable and capable of droplet formation. Solutions are created when the feedstock liquid, termed a solvent, dissolves the product solids. Slurries and dispersions are created when the product solids do not dissolve in the feedstock liquid. The extensive application of spray drying to multiple industries, including agriculture, chemicals, dairy, and pharmaceuticals has resulted in the creation of technologies that aid in feedstock storage, pumping, atomization, drying, and product (powder) collection. An extensive review of the spray drying art is described by Masters (2002), which is incorporated herein by reference.
The competing heat and mass transfer processes central to the creation of spray dried powders significantly contribute to final product attributes. The evaporation of feedstock liquid and the simultaneous increase in droplet temperature (due to heat transfer supplied by the heated drying medium) create complex mechanisms of particle formation. Both feedstock formulation and spray dryer operation determine how solids form from the atomized feedstock droplet. A variety of final particle shapes, including smooth and ruptured spheres and irregular/fragmented forms, has been reported.
It can be difficult to produce dense, free-flowing spray dried powders when the feedstock comprises plastic film-forming materials (e.g., polymers). After atomization, the initial droplet surface is freely saturated with solvent, which readily evaporates in the drying medium. With subsequent solvent loss, a film may be produced, and for additional drying to occur, solvent must diffuse through this layer for evaporation to occur. Eventually, the film layer may sufficiently impede solvent diffusion/evaporation. This condition, known as case hardening, is undesirable for two reasons: First, it can be exceedingly difficult to remove additional solvent from case-hardened particles. Extensive secondary drying may be required to reduce the solvent content to acceptable levels. Second, the case-hardened particle may balloon in size as the trapped solvent is heated by the drying medium. Consequently, spray dried powders of film-forming materials may suffer from low bulk and tapped density in addition to unacceptably high residual solvent content. To resolve these limitations, those skilled in the art may have to rely on special nozzles or drying methods to limit temperature gradients that might otherwise induce case hardening and its negative consequences. Nonetheless, further drying steps may be needed to reduce this residual solvent content to levels acceptable for the finished product. Thus, there exists the need for methods to reduce case hardening in order to ease production and improve product quality.
An additional challenge to the production of spray dried powders is the atomization of discrete feedstock droplets. It is well known by those skilled in the art that viscous feedstocks may not atomize cleanly. Shear forces, necessary to break-up the feed into separate droplets, may be insufficient to overcome viscous forces at the point of atomization. As a result, the atomization device produces viscous threads, which can solidify in the drying medium. Such threads significantly reduce product quality due to their variable nature and poor flowability. The problem of high feedstock viscosity can be resolved by reducing solids concentration (which undesirably reduces production throughput), or by increasing feedstock temperature. The practice of heating the aqueous feedstocks, common in the milk and other foods industries, simultaneously helps to reduce microbial contamination. The effect of heated feedstock may increase or decrease powder density, depending on whether or not the increased feed temperature deaerates the feed [Masters, 2002].
Yet another disadvantage of conventional spray drying technology is the restriction imposed upon the feedstock formulation. It may be desired, for a variety of product quality and performance reasons, to incorporate preferred components in the feedstock to be spray dried. However, a lack of mutual solubilities in a common solvent may make it difficult or impossible to achieve. Other times, satisfactory solubility between feedstock components is achieved only through difficult-to-use or toxic solvents. For example, if the common solvent has an exceedingly high boiling point (e.g., dimethylsulfoxide, 189° C.), it can be difficult to remove the solvent through spray drying alone; the spray dried powder (if it can be produced) then requires extensive secondary drying. Alternatively, the common solvent may comprise an ICH Class I or II solvent (e.g., dichloromethane), whose toxicological and environmental concerns warrant special processing considerations. Thus, there exists the need for advanced spray drying processes to facilitate solubility and reduce or eliminate the need for difficult-to-use or toxic solvents.
Even when a feedstock formulation is achievable using conventional techniques, the performance of the spray dried powder may suffer from unacceptable properties, including: particle size, particle size distribution, bulk and/or tapped density, rate of active release, and/or extent of active release. Effective reformulation to resolve such properties may not be afforded using conventional techniques known to one skilled in the art. Thus, advanced methods are needed to increase formulation flexibility and create these desired compositions.
Contrary to this teaching, a utile process may not be provided for feedstocks comprising organic solvents when the drying chamber is maintained above the boiling point of the organic solvent—the nozzle may clog under these conditions. Accordingly, it may be advantageous to maintain the drying chamber at a temperature less than the boiling point of the solvent. Surprisingly, the condition of a heated drying medium may be unnecessary in order to produce a powder product; the drying chamber need not be appreciably heated above ambient conditions, and in fact the process gas may have to cool droplets of the high-energy feedstock.